In a population based study of AD, we have screened all elderly residents of Wadi Ara, an Arab community near Tel Aviv in northern Israel, and observed an unusually high prevalence (20.5% of those >60 years, 60.5% of those >85 years). This prevalence is higher than that found anywhere else in the world, even after adjustment for age, education and gender, and apparently is not due to increased frequency of the APOE epsilon-4 allele. We hypothesize that the increased prevalence of AD in this genetic isolate is caused by the presence of AD susceptibility alleles which are over-represented because of mating patterns in this closed population which has few founders. In this application we propose to study extensively all persons residing in this community ages 60 and older (numbering 855 at the time of the last survey including 168 persons meeting NINDS/ADRDA criteria for AD). We will obtain from each subject risk/protective factor data (including smoking, blood pressure, head trauma, education, diet, physical and mental activity levels, occupation and medication history) and blood samples for biochemical and DNA studies. Family informants will be used to construct detailed pedigrees. Our scientific aims are: (1) Estimate the life-time risk of AD in first-degree relatives of prevalent cases using survival techniques and compare these estimates to those obtained for relatives of cognitively normal subjects and for relatives of AD cases in other populations; (2) Localize the gene(s) causing AD in this population using a homozygosity mapping approach. In order to rapidly screen for markers linked to the disease, one AD affected and one elderly nondemented from each of several families from the same tribal group (hamula) will be genotyped with 400 polymorphic microsatellite markers spaced less than 10 cM apart. Suspect chromosomal regions will be pursued by genotyping all subjects individually with markers spaced at 2 cM intervals. A variety of analytical techniques including both parametric (lod score) and non-parametric (affected relative, sib-transmission-disequilibrium and allele-frequency-dependent homozygosity mapping) approaches will be employed to assess the marker data for linkage to AD; (3) Examine genes from candidate regions identified in aim 2 by SSCP/CSGE; and direct sequencing for polymorphisms which may directly influence AD susceptibility; (4) Analyze the effects of non-genetic factors (singly and in combination with each other and with linked genetic markers or candidate gene polymorphisms) on risk of AD. Identifying specific genes and elucidating their mechanisms and the nature of gene/environment interactions will be a major achievement. Results from this study may have immediate impact on the development of new treatment or prevention strategies.